The Clinical Psychopharmacology Section conducts pre-clinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK is the synthesis and evaluation of potential treatment medications for cocaine addiction. The strong association of high risk behaviors related to the spread of HIV with cocaine addiction makes the effort to develop cocaine treatment medications highly related to the fight against AIDS. In this fiscal year we continued the effort to develop analogs of GBR12909 as putative cocaine antagonists or cocaine substitution-type medications. Previous studies in Rhesus monkeys showed that daily administration of GBR12909 suppresses cocaine self-administration without the development of tolerance. This year, a long-acting ester derivative of GBR12909 1-[2-[Bis(4- fluorophenyl)methoxy[ethyl]-4-(3-hydroxy-3-phenylpropyl)piperaziny] decanoate, was prepared. A single administration of this agent almost eliminated cocaine self-administration in Rhesus monkeys for about 28 days. Other efforts identified releasers of dopamine and serotonin as potential treatment agents for cocaine addiction and 5-HT4 antagonists as potential treatments of cocaine-induced cardiac arrhythmia. Collaborative studies continued to characterize the neurochemical and neuroendocrine effects of ibogaine. Other studies identified a novel cocaine binding sites in human brain which has low affinity for most inhibitors of classic biogenic amine transporters. Clinical and laboratory experiments continued to demonstrate robust changes in the serotonergic systems during cocaine withdrawal. These results support the hypothesis that cocaine withdrawal is associated with a dual deficit of dopamine and serotonin and provide a strong rationale for the treatment of cocaine addiction with medications which affect both neurotransmitters.